1. Field of the Invention
The present invention relates generally to novel 1,4-dihydropyridine derivatives and more particularly, it relates to the 2,6-di-lower alkyl-4-substituted phenyl-1,4-dihydropyridine-3-carboxylic acid aminoalkyl ester derivatives represented by the general formula ##SPC1##
Wherein R represents a hydrogen atom or a lower alkyl group; R.sup.1 and R.sup.2, which may be the same or different, each represents a lower alkyl group; R.sup.3 represents a phenyl group, a phenyl lower alkyl group, a phenyl lower alkyl group substituted with a halogen atom, a lower alkyl group or a lower alkoxy group, R.sup.4 represents a hydrogen atom or a lower alkyl group; A represents a lower alkylene group; R.sup.5 represents a lower alkyl group, a lower alkoxy group, or a lower alkoxy group substituted with a lower alkoxy group or ##STR1## and R.sup.6 represents a nitro group or a trifluoromethyl group.
The compounds of this invention have excellent cerebral vascular dilator activity.
2. Description of the Prior Art
As 1,4-dihydropyridine-3,5-dicarboxylic acid derivatives, 4-nitrophenyl-2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylic acid dialkyl esters have been known from old as described in, for example, Chem. Ber. 20, 1338-1343 (1887) [4-(2',3' or 4' -nitrophenyl)-2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylic acid diethyl ester] and J. Am. Chem. Soc., 71, 4003-4007 (1949) [4-(3'-nitrophenyl)-2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylic acid dimethyl, diethyl or di-n-butyl ester].
And it is known that 4-(2'-nitrophenyl)-2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylic acid dimethyl ester shows coronary vasodilator activity (U.S. Pat. No. 3,644,627).
Further, the compounds having pyridyl or pyrimidyl group instead of nitrophenyl at 4-position in the above-mentioned compounds have been also prepared (U.S. Pat. No. 3,470,297 or U.S. Pat. No. 3,511,837). However, free compounds of these compounds are poorly water-soluble and when these compounds are dissolved in water in the form of their salts, they are unstable (cf. U.S. Pat. No. 3,488,359 col. 2, lines 26-30).
Though it is described in U.S. Pat. No. 3,488,359 that hydroxyalkyl ester or alkoxyalkyl ester are soluble and stable in water either in the free form or in the form of their salts (col. 2, lines 22-25), practical example showing the excellent water-solubility of these esters is not described in the specification (especially, it is not described that the compounds are soluble in water at PH ranges wherein injection can be prepared).
Some other similar types of compounds are known [U.S. Pat. No. 3,511,837 (4-pyrimidyl-1,4-dihydropyridine derivatives) U.S. Pat. No. 3,691,177 (Cyanophenyl-1,4-dihydropyridine derivatives), German Offenlegungsschrift No. 1,813,436 (N-alkyl-1,4-dihydropyridine derivatives), No. 1,923,990 (N-alkyl-1,4-dihydropyridine derivatives), No. 1,963,185 (4-nitro and other group substituted phenyl-1,4-dihydropyridine derivatives), No. 1,963,186 (Sulfur containing 4-aryl-1,4-dihydropyridine derivatives), No. 2,005,116 (1,4-dihydropyridine-3,5-dicarboxylic acid unsaturated alkyl esters), No. 2,003,146 (3-alkanoyl-1,4-dihydropyridine-5-carboxylic acid esters)].
As a result of researching a series of these compounds, it was published in Naturwissenschaften 58, (11)578(1971) that 4-(2'-nitrophenyl)-2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylic acid dimethyl ester) generic name: Nifedipine) shows much excellent coronary vasodilator activity and spasmolytic activity.
Further, it is known that 1,4-dihydro-2,6-dimethyl-4-(2'-trifluoromethylphenyl)-3,5-pyridine dicarboxylic acid diethyl ester shows hypotensive activity (U.S. Pat. No. 3,511,837). However, this compound is very poorly water-soluble [J. Pharm. Sci., 61, (10) 1686(1972)].